Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods

Abstract

Compounds are provided having the formula (I) wherein: n is 0, 1 or 2; m is 0, 1 or 2; the sum of n+m less then or equal to 2; the dashed bonds forming a cyclopropyl ring can only be present when Y is CH; X is H or CN; Y is CH, CH 2 , CHF, CF 2 , O, S, SO, or SO 2 ; and A is adamantyl. Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

1. A compound of formula (I) 
                 
 wherein:  
 n is 0, 1 or 2;  
 m is 0, 1 or 2;  
 the sum of n plus m is less then or equal to 2;  
 the dashed bonds forming a cyclopropyl ring when Y is CH;  
 X is hydrogen or CN;  
 Y is CH, CH 2 , CHF, CF 2 , O, S, SO, or SO 2    
 A is adamantyl which can be optionally substituted with from zero to six substituents each independently selected from OR 1 , NR 1 R 2 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;  
 R 1  and R 2  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl;  
 including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof,  
 with the proviso that the compound of formula (I) is not selected from 
                 
 
 
     
     
       2. The compound as defined in  claim 1  selected from 
                 
 
     
     
       3. The compound as defined in  claim 1  selected from 
                 
 
     
     
       4. A compound of the formula 
                 
 
     
     
       5. A compound of the formula 
                 
 
     
     
       6. A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
       7. A pharmaceutical composition that inhibits DPP-IV containing a compound as defined in  claim 1 .